The major histocompatibility complex of the mouse (H-2) can be identified by several criteria: immunization across H-2 differences leads to production of humoral alloantibodies which can be used to identify serologically the H-2 antigens; skin transplantation across the H-2 barrier leads to rapid graft rejection; injection of immunologically competent donor cells into recipients which are incapable of mounting an immune response against these cells, results in graft-versus-host reaction; and mixing cells in mixed lymphocyte culture results in a proliferative response which can be assayed by the incorporation of radioactive thymidine. Originally it was thought that the different criteria were identifying the same artigens. Preliminary results obtained by the principal investigator and by others indicate that this need not be so and that the different regions of the H-2 complex could have different functions. It is the aim of the proposed program to define the genetic organization of the H-2 complex, to determine the function of the individual H-2 regions, to determine the functional interrelationship (if any) of the different H-2 regions, and to obtain some clues to the evolutionary significance of clustering of genes into major histocompatibility complexes. The genetic organization of the H-2 complex will be studied by serological and transplantation analysis of similar H-2 recombinants. The function and functional interrelationship of the H-2 regions will be analyzed using a panel of strain combinations to which an arseral of assays for cellular immunity will be applied. The evolutionary significance of the H-2 complex will be examined by serological, transplantation and genetic analysis of H-2 chromosomes derived from wild mice. It is expected that elucidation of genetic and functional organization of the H-2 complex will help to understand homologous complexes in other species, especially the HL-A system in man.